Just how common is CLL?

Just exactly how common is CLL?

Most articles about CLL begin with the sentence, “CLL is the commonest type of leukaemia in the Western world.” However, the apparent incidence of CLL has fluctuated widely over the years. In Hansen’s magnum opus [1] published in 1973 and based on 189 cases of CLL followed for a long time, he reports on previous studies that found an incidence of 5.5 per 100,000 in 1949, 6.6 per 100,000 over the period 1943-52, and 6.4 per 100,000 between 1958 and 1961. In 1964 a Danish study found an incidence of 7.8 per 100,000.

This was in the days before immunophenotyping when any lymphocytosis over 10,000 per microlitre of relatively appropriate morphology was designated CLL. In a retrospective examination of patients previously diagnosed in our own unit we have identified patients misdiagnosed as CLL who in fact had splenic marginal zone lymphoma, mantle cell lymphoma, follicular lymphoma, small cell Sezary syndrome and T-cell prolymphocytic leukaemia. In our work as a reference center we have recognised that these types of mistakes were not rare. Immunophenotyping has excluded the majority of interlopers and as a result the perceived incidence of CLL fell between the nineteen seventies and nineteen nineties. Sgambati et al [2] reporting on statistics from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) Program described a fall in incidence rates for CLL for white males from 4.2 per 100,000 to 3.2 per 100,000 between 1973 and 1976 while the rate for white females fell from 3.8 to 2.6 over the same period. The rates for those of African-American, Hispanic or Asian origin were much lower.

Exactly how many cases of CLL are collected depends on how assiduous is the collection. Simply relying on death certificates or hospital admissions will miss all those early stage patients that never progress and never require treatment. Between 1984 and 1988 Cartwright et al [3] enlisted the help of hematologists performing blood tests for one third of the population of England and Wales to register every new diagnosis of CLL. The annual incidence was 5.54 per 100,000 with a male to female ratio of 1.95. There was no temporal variation, but a threefold difference between districts. Racial differences could not explain the discrepancies, though districts where the disease was commoner tended to have more old people. What was noticeable was that the disease was apparently commoner where the hematologists took a special interest in the disease, suggesting that such specialists would be more likely to make the diagnosis with a relatively low lymphocyte count that less obsessed doctors might pass as normal.

Guidelines for the diagnosis of CLL were published in 1988 by a National Cancer Institute Working Group (NCI-WG) [4] and in 1989 by the International Workshop on CLL (IWCLL) [5]. The former required a lymphocytosis of >5 x 109/L but the latter a lymphocytosis of >10 x 109/L. This confusion was removed by the 1996 guidelines published by the NCI-WG [6] which settled on a lymphocytosis of >5 x 109/L but has been further complicated by the 2008 guidelines published by the IWCLL [7] which raise the threshold to a B-cell lymphocytosis of >5 x 109/L.
In 2002 Rawstron et al [8] discovered that 3.5% of the population over the age of 40 harbors a population of cells immunophenotypically similar to those of CLL. More sensitive techniques suggest that this percentage might be as high as 12% [9]. This new entity, monoclonal B-cell lymphocytosis (MBL), seems to precede most new cases of CLL [10], but clearly most cases never progress to become CLL. Since individuals with MBL may have up to 5 x 109/L B lymphocytes, the new threshold for CLL was absolutely essential to distinguish between them.

In this issue of Leukemia Research, Seftel et al [11] have analyzed the effect that diagnosis by immunophenotyping has had on the incidence of CLL according to the 1996 criteria. The SEER figures for the period 1993-2004 give a combined incidence of CLL and small lymphocytic lymphoma (SLL) of 5.13 per 100,000 [12]. SLL is essentially the same disease as CLL in which the lymphoid expansion is confined to lymph nodes and not present in the blood. It differs from MBL in having definite lymph node enlargement. For the period 1996-2005 the Public Health Agency of Canada, using data from provincial cancer registries reported an incidence of 5.9/100,000 [13]. Seftel et al assembled the data from the provincial cancer registry at CancerCare Manitoba and supplemented these with flow cytometry reports from the two tertiary referral centers in Winnipeg. In both cases the data covered the period from January 1st 1998 to December 31st 2003.

The results of their study demonstrated the fragility of data from cancer registries. Although they assembled 813 patients, 14.5% had to be excluded for administrative reasons, mainly because the diagnosis had been made before the study period. This is a common problem, because diagnosis by a haematologist is very likely to predate a patient being brought to the attention of a cancer registry. A further 9.7% were excluded because of a wrong diagnosis, most commonly marginal zone lymphoma. Despite these exclusions the apparent incidence of CLL has risen. Over the study period as flow cytometry was more regularly used, the annual incidence went from 6.73/100,000 in 1998 to 9.40/100,000 in 2003. It was this apparent increase in early stage CLL that prompted Hoffbrand and Hamblin in 2007 to warn that patients were having the label ‘leukemia’ attached to them when they might realistically expect and normal and healthy lifespan [14].

The new 2008 guidelines for the diagnosis of CLL will have the effect of reducing the incidence since a B-cell lymphocytosis of 5x109/L roughly equates to a lymphocytosis of 11x109/L [15]; back to where we were in 1973. The new guidelines has been criticised on the grounds that there would be unintended consequences of cost and access, and that there was no established clinical relevance of making the change [16]. Furthermore, follow-up monitoring of patients with MBL would be more expensive since it would now have to include flow cytometry [16]. However, these criticisms have been rebuffed by the IWCLL working group although they admit that more work needs to be done at the MBL/CLL interface [17].

The true incidence of CLL remains a mystery. We shall have to await studies using the 2008 diagnostic criteria.